Epithelial sodium channels (ENaC) are members of the ENaC/degenerin family of ion channels that includes acid-sensing ion channels (ASIC) in mammals, mechanosensitive degenerin channels in worms, and FMRF-amide peptide-gated channels in mollusks (Kellenger, S. and Schild, L. (2002) Physiol. Rev. 82:735-767). ENaC mediates apical membrane Na+ transport across high resistance epithelia in numerous tissues including kidney, colon, and lung.
ENaC is known to be a heterotrimeric channel comprised of α, β, and γ subunits. This heterotrimeric channel has been hypothesized to be involved in human salty taste perception. Additionally, this channel is involved in the maintenance of extracellular volume and blood pressure, absorption of fluid from the lungs during late stages of gestation, and transduction of salt taste. (See e.g., Rossier, B. C. et al., Annu. Rev. Physiol. 62:877-897 (2002); Alvaraz et al. Annu. Rev. Physiol. 62:573-594 (2000); and Bigiani et al., Prog. Biophys. Mol. Biol. 83:193-225 (2003)).
For example, it is known that mutations in the human ENaC (hENaC), particularly gain of function mutations result in hypertension due to increased renal Na+ reabsorption in Liddle's syndrome (Schild et al., Proc. Natl. Acad. Sci., USA 92:5699-5703 (1995); Shimkets et al., Cell 79:407414 (1994); and Snyder et al., Cell 83:969-98 (1995)). By contrast, it is known that hENaC loss of function mutations result in salt-wasting due to decreased renal Na+ reabsorption in pseudohypoaldosteronism type I (PHA1). (See Grunder et al., EMBO. J. 16:899-907 (1997); and Chang et al., Nat. Genet. 12:248-253 (1996)). The clinical symptoms of salt-wasting include by way of example hyponatremia, hyperkalemia, dehydration, elevated serum aldosterone, and mineralocorticoid unresponsiveness.